Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJYJQJ8)

• DOT Name: E3 ubiquitin-protein ligase ARIH2 (ARIH2)
• Synonyms: ARI-2; Protein ariadne-2 homolog; EC 2.3.2.31; RING-type E3 ubiquitin transferase ARIH2; Triad1 protein
• Gene Name: ARIH2
• Related Disease:
  Acute myelogenous leukaemia
  HIV infectious disease
  leukaemia
  Leukemia
  Age-related macular degeneration
  Glycogen storage disease type II
• UniProt ID: ARI2_HUMAN
• PDB ID: 7OD1; 7ONI
• EC Number: 2.3.2.31
• Pfam ID: PF19422 ; PF01485
• Sequence:
  MSVDMNSQGSDSNEEDYDPNCEEEEEEEEDDPGDIEDYYVGVASDVEQQGADAFDPEEYQ
  FTCLTYKESEGALNEHMTSLASVLKVSHSVAKLILVNFHWQVSEILDRYKSNSAQLLVEA
  RVQPNPSKHVPTSHPPHHCAVCMQFVRKENLLSLACQHQFCRSCWEQHCSVLVKDGVGVG
  VSCMAQDCPLRTPEDFVFPLLPNEELREKYRRYLFRDYVESHYQLQLCPGADCPMVIRVQ
  EPRARRVQCNRCNEVFCFKCRQMYHAPTDCATIRKWLTKCADDSETANYISAHTKDCPKC
  NICIEKNGGCNHMQCSKCKHDFCWMCLGDWKTHGSEYYECSRYKENPDIVNQSQQAQARE
  ALKKYLFYFERWENHNKSLQLEAQTYQRIHEKIQERVMNNLGTWIDWQYLQNAAKLLAKC
  RYTLQYTYPYAYYMESGPRKKLFEYQQAQLEAEIENLSWKVERADSYDRGDLENQMHIAE
  QRRRTLLKDFHDT
• Function: E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3. Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-5-RING ubiquitin ligase complex (ECS complex, also named CRL5 complex) and initiating ubiquitination of ECS substrates: associates with ECS complex and specifically mediates addition of the first ubiquitin on ECS targets. The initial ubiquitin is then elongated. E3 ubiquitin-protein ligase activity is activated upon binding to neddylated form of the ECS complex. Mediates 'Lys-6', 'Lys-48'- and 'Lys-63'-linked polyubiquitination. May play a role in myelopoiesis.
• Tissue Specificity: Widely expressed with higher expression in granulocytes.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
HIV infectious disease	DISO97HC	Strong	Biomarker	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Age-related macular degeneration	DIS0XS2C	Limited	Biomarker	[3]
Glycogen storage disease type II	DISXZPBC	Limited	Biomarker	[3]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase ARIH2 (ARIH2).	[12]

References

• [1] The E3 ubiquitin ligase Triad1 influences development of Mll-Ell-induced acute myeloid leukemia.Oncogene. 2018 May;37(19):2532-2544. doi: 10.1038/s41388-018-0131-5. Epub 2018 Feb 20.
• [2] ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection.Cell Host Microbe. 2019 Jul 10;26(1):86-99.e7. doi: 10.1016/j.chom.2019.05.008. Epub 2019 Jun 25.
• [3] GENETICS OF LARGE PIGMENT EPITHELIAL DETACHMENTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.Retina. 2020 Apr;40(4):663-671. doi: 10.1097/IAE.0000000000002454.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.